Review Article | Published:

Serotonin signalling in the gut—functions, dysfunctions and therapeutic targets

Nature Reviews Gastroenterology & Hepatology volume 10, pages 473486 (2013) | Download Citation

This article has been updated

Abstract

Serotonin (5-HT) has been recognized for decades as an important signalling molecule in the gut, but it is still revealing its secrets. Novel gastrointestinal functions of 5-HT continue to be discovered, as well as distant actions of gut-derived 5-HT, and we are learning how 5-HT signalling is altered in gastrointestinal disorders. Conventional functions of 5-HT involving intrinsic reflexes include stimulation of propulsive and segmentation motility patterns, epithelial secretion and vasodilation. Activation of extrinsic vagal and spinal afferent fibres results in slowed gastric emptying, pancreatic secretion, satiation, pain and discomfort, as well as nausea and vomiting. Within the gut, 5-HT also exerts nonconventional actions such as promoting inflammation and serving as a trophic factor to promote the development and maintenance of neurons and interstitial cells of Cajal. Platelet 5-HT, originating in the gut, promotes haemostasis, influences bone development and serves many other functions. 5-HT3 receptor antagonists and 5-HT4 receptor agonists have been used to treat functional disorders with diarrhoea or constipation, respectively, and the synthetic enzyme tryptophan hydroxylase has also been targeted. Emerging evidence suggests that exploiting epithelial targets with nonabsorbable serotonergic agents could provide safe and effective therapies. We provide an overview of these serotonergic actions and treatment strategies.

Key points

  • Serotonin (5-HT) is an important gastrointestinal signalling molecule that conveys signals from the lumen of the gut to intrinsic and extrinsic sensory neurons, and contributes to synaptic signals in the enteric nervous system

  • Fundamental properties of mucosal 5-HT signalling are altered in response to inflammation and in functional gastrointestinal disorders

  • Actions of 5-HT released from mucosal enterochromaffin cells include stimulation of intrinsic reflexes such as peristalsis, segmentation, secretion and vasodilation

  • 5-HT can also activate signals sent to the CNS that stimulate digestive reflexes and can cause abdominal pain and discomfort, satiety or nausea

  • Mucosal 5-HT can promote intestinal inflammation, and 5-HT in the muscularis propria can promote survival of neurons and interstitial cells of Cajal, and promote neural regeneration

  • As the colonic epithelium is rich in 5-HT-related targets, nonabsorbable drugs that target 5-HT3 receptors, 5-HT4 receptors and tryptophan hydroxylase could serve as safe and effective therapies

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Change history

  • 27 August 2013

    In the original version of this article published online and in print, the permission line for Figure 2 was omitted. The error has been corrected for the HTML and PDF versions of the article.

References

  1. 1.

    & Ricerche sul secreto delle cellule enterocromaffini [Italian]. Boll. d Soc. Med.-chir. Pavia 51, 357–363 (1937).

  2. 2.

    , & Partial purification of the vasoconstrictor in beef serum. J. Biol. Chem. 174, 735–741 (1948).

  3. 3.

    The discovery of serotonin and its role in neuroscience. Neuropsychopharmacology 21, 2S–8S (1999).

  4. 4.

    & The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology 132, 397–414 (2007).

  5. 5.

    , & Review article: intestinal serotonin signalling in irritable bowel syndrome. Aliment. Pharmacol. Ther. 23, 1067–1076 (2006).

  6. 6.

    , & Sensory mechanisms: transmitters, modulators and reflexes. Neurogastroenterol Motil. 16 (Suppl. 1), 60–63 (2004).

  7. 7.

    et al. Disruption of the nonneuronal tph1 gene demonstrates the importance of peripheral serotonin in cardiac function. Proc. Natl Acad. Sci. USA 100, 13525–13530 (2003).

  8. 8.

    & A unique central tryptophan hydroxylase isoform. Biochem. Pharmacol. 66, 1673–1680 (2003).

  9. 9.

    , & Immunoelectron microscopic study of the luminal release of serotonin from rat enterochromaffin cells induced by high intraluminal pressure. Histochem. Cell Biol. 108, 105–113 (1997).

  10. 10.

    , , & Serotonin (5-HT) release and uptake measured by real-time electrochemical techniques in the rat ileum. Am. J. Physiol. Gastrointest. Liver Physiol. 295, G1228–G1236 (2008).

  11. 11.

    et al. Activation of colonic mucosal 5-HT4 receptors accelerates propulsive motility and inhibits visceral hypersensitivity. Gastroenterology 142, 844–854 e4 (2012).

  12. 12.

    , , , & In vitro continuous amperometric monitoring of 5-hydroxytryptamine release from enterochromaffin cells of the guinea pig ileum. Analyst 132, 41–47 (2007).

  13. 13.

    & Mast cell-nerve axis with a focus on the human gut. Biochim. Biophys. Acta 1822, 85–92 (2012).

  14. 14.

    et al. Immunohistochemical localization of tryptophan hydroxylase in the human and rat gastrointestinal tracts. J. Comp. Neurol. 411, 654–665 (1999).

  15. 15.

    , , , & Human mast cells are capable of serotonin synthesis and release. J. Allergy Clin. Immunol. 119, 498–499 (2007).

  16. 16.

    , , & Clinical correlates of blood serotonin levels in patients with mastocytosis. Eur. J. Clin. Invest. 38, 953–958 (2008).

  17. 17.

    et al. Localization and function of a 5-HT transporter in crypt epithelia of the gastrointestinal tract. J. Neurosci. 16, 2352–2364 (1996).

  18. 18.

    , , , & Guinea pig 5-HT transporter: cloning, expression, distribution, and function in intestinal sensory reception. Am. J. Physiol. 275, G433–G448 (1998).

  19. 19.

    et al. Maintenance of serotonin in the intestinal mucosa and ganglia of mice that lack the high-affinity serotonin transporter: Abnormal intestinal motility and the expression of cation transporters. J. Neurosci. 21, 6348–6361 (2001).

  20. 20.

    et al. Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and irritable bowel syndrome. Gastroenterology 126, 1657–1664 (2004).

  21. 21.

    et al. Cloning and expression of a functional serotonin transporter from rat brain. Nature 354, 66–70 (1991).

  22. 22.

    , , & Serotonin transporter: gene, genetic disorders, and pharmacogenetics. Mol. Interv. 4, 109–123 (2004).

  23. 23.

    , , , & Serotonin availability is increased in mucosa of guinea pigs with TNBS-induced colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 285, G207–G216 (2003).

  24. 24.

    , , , & High mucosal serotonin availability in neonatal guinea pig ileum is associated with low serotonin transporter expression. Gastroenterology 132, 2438–2447 (2007).

  25. 25.

    et al. Serotonin transporter function and expression are reduced in mice with TNBS-induced colitis. Neurogastroenterol. Motil. 17, 565–574 (2005).

  26. 26.

    , & Alternative non-coding exons support serotonin transporter mRNA expression in the brain and gut. J. Neurochem. 82, 336–344 (2002).

  27. 27.

    et al. Neurochemical classification of myenteric neurons in the guinea-pig ileum. Neuroscience 75, 949–967 (1996).

  28. 28.

    & Ultrastructural examination of the targets of serotonin-immunoreactive descending interneurons in the guinea pig small intestine. J. Comp. Neurol. 356, 101–114 (1995).

  29. 29.

    & Neurons with 5-hydroxytryptamine-like immunoreactivity in the enteric nervous system: their projections in the guinea-pig small intestine. Neuroscience 7, 341–349 (1982).

  30. 30.

    , , & Multiple mechanisms of fast excitatory synaptic transmission in the enteric nervous system. J. Auton. Nerv. Syst. 81, 97–103 (2000).

  31. 31.

    , & ATP and 5-HT are the principal neurotransmitters in the descending excitatory reflex pathway of the guinea-pig ileum. Neurogastroenterol. Motil. 14, 255–264 (2002).

  32. 32.

    , & Investigation of the role of 5-HT3 and 5-HT4 receptors in ascending and descending reflexes to the circular muscle of guinea-pig small intestine. Br. J. Pharmacol. 112, 1095–1100 (1994).

  33. 33.

    , & Peripheral neural serotonin receptors: identification and characterization with specific antagonists and agonists. Proc. Natl Acad. Sci. USA 83, 9799–9803 (1986).

  34. 34.

    , , & Specific antagonism of enteric neural serotonin receptors by dipeptides of 5-hydroxytryptophan: evidence that serotonin is a mediator of slow synaptic excitation in the myenteric plexus. J. Neurosci. 5, 1769–1780 (1985).

  35. 35.

    , & Slow excitatory post-synaptic potentials in myenteric AH neurons of the guinea-pig ileum are reduced by the 5-hydroxytryptamine7 receptor antagonist SB 269970. Neuroscience 134, 975–986 (2005).

  36. 36.

    et al. Impaired synthesis or cellular storage of norepinephrine, dopamine, and 5-hydroxytryptamine in human inflammatory bowel disease. Dig Dis. Sci. 47, 216–224 (2002).

  37. 37.

    , , & Colonic endocrine cells in inflammatory bowel disease. J. Intern. Med. 242, 413–419 (1997).

  38. 38.

    et al. Serotonin signaling in diverticular disease. J. Gastrointest. Surg. 12, 1439–1445 (2008).

  39. 39.

    et al. Abnormalities of serotonin metabolism and their relation to symptoms in untreated celiac disease. Clin. Gastroenterol. Hepatol. 4, 874–881 (2006).

  40. 40.

    et al. Impaired uptake of serotonin by platelets from patients with irritable bowel syndrome correlates with duodenal immune activation. Gastroenterology 140, 1434–1443 e1 (2011).

  41. 41.

    , , , & Serotonin signaling is altered in irritable bowel syndrome with diarrhea but not in functional dyspepsia in pediatric age patients. Gastroenterology 139, 249–258 (2010).

  42. 42.

    , , & Ileitis alters neuronal and enteroendocrine signalling in guinea pig distal colon. Gut 56, 186–194 (2007).

  43. 43.

    , , , & Analysis of real-time serotonin (5-HT) availability during experimental colitis in mouse. Am. J. Physiol. Gastrointest. Liver Physiol. 298, G446–G455 (2010).

  44. 44.

    , , , & Consequences of Citrobacter rodentium infection on enteroendocrine cells and the enteric nervous system in the mouse colon. Cell. Microbiol. 8, 646–660 (2006).

  45. 45.

    et al. Enterochromaffin cell hyperplasia and decreased serotonin transporter in a mouse model of postinfectious bowel dysfunction. Neurogastroenterol. Motil. 17, 863–870 (2005).

  46. 46.

    , , & IFN-γ and TNF-α decrease serotonin transporter function and expression in Caco2 cells. Am. J. Physiol. Gastrointest. Liver Physiol. 292, G779–784 (2007).

  47. 47.

    et al. Enteropathogenic Escherichia coli infection inhibits intestinal serotonin transporter function and expression. Gastroenterology 137, 2074–2083 (2009).

  48. 48.

    et al. Functional bowel disorders. Gastroenterology 130, 1480–1491 (2006).

  49. 49.

    , , , & Enterochromaffin cells and 5-HT signaling in the pathophysiology of disorders of gastrointestinal function. Curr. Opin. Investig. Drugs 5, 55–60 (2004).

  50. 50.

    et al. Alterations in expression of p11 and SERT in mucosal biopsy specimens of patients with irritable bowel syndrome. Gastroenterology 132, 17–25 (2007).

  51. 51.

    , , & SERT and TPH-1 mRNA expression are reduced in irritable bowel syndrome patients regardless of visceral sensitivity state in large intestine. Am. J. Physiol. Gastrointest. Liver Physiol. 302, G1053–G1060 (2012).

  52. 52.

    , , , & Increased platelet depleted plasma 5-hydroxytryptamine concentration following meal ingestion in symptomatic female subjects with diarrhoea predominant irritable bowel syndrome. Gut 52, 663–670 (2003).

  53. 53.

    , , , & Altered 5-hydroxytryptamine signaling in patients with constipation- and diarrhea-predominant irritable bowel syndrome. Gastroenterology 130, 34–43 (2006).

  54. 54.

    et al. Abnormalities of 5-hydroxytryptamine metabolism in irritable bowel syndrome. Clin. Gastroenterol. Hepatol. 3, 349–357 (2005).

  55. 55.

    et al. Serotonin transporter activity and serotonin concentration in platelets of patients with irritable bowel syndrome: effect of gender. J. Gastroenterol. 45, 389–398 (2010).

  56. 56.

    et al. Platelet serotonin transporter in patients with diarrhea-predominant irritable bowel syndrome both before and after treatment with alosetron. Am. J. Gastroenterol. 98, 2705–2711 (2003).

  57. 57.

    et al. Mucosal serotonin signaling is altered in chronic constipation but not in opiate-induced constipation. Am. J. Gastroenterol. 105, 1173–1180 (2010).

  58. 58.

    , , , & Serotonin and 5-hydroxyindoleacetic acid are increased in the sigmoid colon in severe idiopathic constipation. Gastroenterology 98, 1219–1225 (1990).

  59. 59.

    , , & Effects of serotonin transporter inhibition on gastrointestinal motility and colonic sensitivity in the mouse. Neurogastroenterol. Motil. 18, 464–471 (2006).

  60. 60.

    et al. Selective effects of serotonergic psychoactive agents on gastrointestinal functions in health. Am. J. Physiol. Gastrointest. Liver Physiol. 284, G130–G137 (2003).

  61. 61.

    et al. Prolonged stationary colonic motility recording in seven patients with severe constipation secondary to antidepressants. Neurogastroenterol. Motil. 12, 149–154 (2000).

  62. 62.

    , , , & Influence of acute serotonin reuptake inhibition on colonic sensorimotor function in man. Aliment. Pharmacol. Ther. 23, 265–274 (2006).

  63. 63.

    , & Irritable bowel syndrome: methods, mechanisms, and pathophysiology. The confluence of increased permeability, inflammation, and pain in irritable bowel syndrome. Am. J. Physiol. Gastrointest. Liver Physiol. 303, G775–G785 (2012).

  64. 64.

    et al. Allelic variation of human serotonin transporter gene expression. J. Neurochem. 66, 2621–2624 (1996).

  65. 65.

    & The functional impact of SLC6 transporter genetic variation. Annu. Rev. Pharmacol. Toxicol. 47, 401–441 (2007).

  66. 66.

    , & Meta-analysis: a functional polymorphism in the gene encoding for activity of the serotonin transporter protein is not associated with the irritable bowel syndrome. Aliment. Pharmacol. Ther. 26, 979–986 (2007).

  67. 67.

    et al. Serotonin transporter gene promoter region polymorphisms and serotonin transporter expression in the colonic mucosa of irritable bowel syndrome patients. Neurogastroenterol. Motil. 24, 560–565 (2012).

  68. 68.

    et al. Relationship of SERT polymorphisms to depressive and anxiety symptoms in irritable bowel syndrome. Biol. Res. Nurs. 9, 161–169 (2007).

  69. 69.

    et al. The serotonin transporter polymorphism rs25531 is associated with irritable bowel syndrome. Dig. Dis. Sci. 54, 2663–2670 (2009).

  70. 70.

    & Observations concerning the action of 5-hydroxytryptamine on the peristaltic reflex. Br. J. Pharmacol. Chemother. 13, 444–457 (1958).

  71. 71.

    & The action of 5-hydroxytryptamine, 5-hydroxytryptophan and reserpine on intestinal peristalsis in anaesthetized guinea-pigs. J. Physiol. 146, 29–53 (1959).

  72. 72.

    & The release of 5-hydroxytryptamine in relation to pressure exerted on the intestinal mucosa. J. Physiol. 146, 18–28 (1959).

  73. 73.

    & The effect of intraluminal application of 5-hydroxytryptamine and 5-hydroxytryptophan on peristalsis; the local production of 5-HT and its release in relation to intraluminal pressure and propulsive activity. J. Physiol. 140, 381–407 (1958).

  74. 74.

    , & Distinct 5-HT receptors mediate the peristaltic reflex induced by mucosal stimuli in human and guinea pig intestine. Gastroenterology 111, 1281–1290 (1996).

  75. 75.

    , , & Stroking human jejunal mucosa induces 5-HT release and Cl secretion via afferent neurons and 5-HT4 receptors. Am. J. Physiol. 277, G515–G520 (1999).

  76. 76.

    Real-time detection of serotonin release from enterochromaffin cells of the guinea-pig ileum. Neurogastroenterol. Motil. 16, 511–514 (2004).

  77. 77.

    , , , & Mechanical stimulation activates Galphaq signaling pathways and 5-hydroxytryptamine release from human carcinoid BON cells. J. Clin. Invest. 108, 1051–1059 (2001).

  78. 78.

    , & Propulsion in guinea pig colon induced by 5-hydroxytryptamine (HT) via 5-HT4 and 5-HT3 receptors. J. Pharmacol. Exp. Ther. 288, 93–97 (1999).

  79. 79.

    , , , & Localized release of serotonin (5-hydroxytryptamine) by a fecal pellet regulates migrating motor complexes in murine colon. Gastroenterology 136, 1328–1338 (2009).

  80. 80.

    , & Nicotinic transmission at functionally distinct synapses in descending reflex pathways of the rat colon. Neurogastroenterol. Motil. 15, 161–171 (2003).

  81. 81.

    , & Participation of 5-HT3, 5-HT4, and nicotinic receptors in the peristaltic reflex of guinea pig distal colon. Am. J. Physiol. 271, G849–G857 (1996).

  82. 82.

    , , & The function of 5-HT3 receptors on colonic transit in rats. Obes. Res. 3 (Suppl. 5), 801S–810S (1995).

  83. 83.

    et al. GR38032F (ondansetron), a selective 3803380338035HT3 receptor antagonist, slows colonic transit in healthy man. Dig. Dis. Sci. 35, 477–480 (1990).

  84. 84.

    , & Involvement of the 5-HT3 receptor in CRH-induce defecation in rats. Am. J. Physiol. 274, G827–G831 (1998).

  85. 85.

    Desensitization of the peristaltic reflex induced by mucosal stimulation with the selective 5-HT4 agonist tegaserod. Am. J. Physiol. Gastrointest. Liver Physiol. 290, G319–G327 (2006).

  86. 86.

    et al. Essential roles of enteric neuronal serotonin in gastrointestinal motility and the development/survival of enteric dopaminergic neurons. J. Neurosci. 31, 8998–9009 (2011).

  87. 87.

    & Release of 5-hydroxytryptamine from the mucosa is not required for the generation or propagation of colonic migrating motor complexes. Gastroenterology 138, 659–670 (2010).

  88. 88.

    et al. Mechanisms underlying distension-evoked peristalsis in guinea pig distal colon: is there a role for enterochromaffin cells? Am. J. Physiol. Gastrointest. Liver Physiol. 301, G519–G527 (2011).

  89. 89.

    , , & Serotonin (5-HT) and cholecystokinin (CCK) mediate nutrient induced segmentation in guinea pig small intestine. Am. J. Physiol. Gastrointest. Liver Physiol. 304, G749–G761 (2013).

  90. 90.

    Neurotransmitters in neuronal reflexes regulating intestinal secretion. Ann. NY Acad. Sci. 915, 77–80 (2000).

  91. 91.

    , & 5-HT activates neural reflexes regulating secretion in the guinea-pig colon. Neurogastroenterol. Motil. 9, 181–186 (1997).

  92. 92.

    & Role for 5-HT and ACh in submucosal reflexes mediating colonic secretion. Am. J. Physiol. 269, G346–G351 (1995).

  93. 93.

    , & Mediation of neurogenic ion transport by acetylcholine, prostanoids and 5-hydroxytryptamine in porcine ileum. Eur. J. Pharmacol. 519, 285–289 (2005).

  94. 94.

    Mucosal protection through active intestinal secretion: neural and paracrine modulation by 5-hydroxytryptamine. Behav. Brain Res. 73, 193–197 (1996).

  95. 95.

    , & Serotonin increases protective duodenal bicarbonate secretion via enteric ganglia and a 5-HT4-dependent pathway. Scand. J. Gastroenterol. 41, 1279–1289 (2006).

  96. 96.

    & Submucosal secretomotor and vasodilator reflexes. Neurogastroenterol. Motil. 16 (Suppl. 1), 39–43 (2004).

  97. 97.

    , & Activation of 5-HT1P receptors on submucosal afferents subsequently triggers VIP neurons and chloride secretion in the guinea-pig colon. J. Auton. Nerv. Syst. 66, 105–110 (1997).

  98. 98.

    , , & Actions of serotonin antagonists on cholera-toxin-induced intestinal fluid secretion. Acta Physiol. Scand. 145, 229–237 (1992).

  99. 99.

    5-Hydroxytryptamine, enterotoxins, and intestinal fluid secretion. Gastroenterology 115, 1009–1012 (1998).

  100. 100.

    , , & Involvement of serotonin and calcium channels in the intestinal fluid secretion evoked by bile salt and cholera toxin. Br. J. Pharmacol. 127, 887–894 (1999).

  101. 101.

    , & Involvement of nerves and calcium channels in the intestinal response to Clostridium difficile toxin A: an experimental study in rats in vivo. Gut 49, 56–65 (2001).

  102. 102.

    , , & Serotonin and vasoactive intestinal peptide antagonists attenuate rotavirus diarrhoea. Gut 53, 952–957 (2004).

  103. 103.

    , & Calretinin immunoreactivity in cholinergic motor neurones, interneurones and vasomotor neurones in the guinea-pig small intestine. Cell Tissue Res. 263, 471–481 (1991).

  104. 104.

    , & Changes in surviving nerve fibers associated with submucosal arteries following extrinsic denervation of the small intestine. Cell Tissue Res. 253, 647–656 (1988).

  105. 105.

    Myenteric neurons activate submucosal vasodilator neurons in guinea pig ileum. Am. J. Physiol. Gastrointest. Liver Physiol. 279, G380–G387 (2000).

  106. 106.

    , & Mucosal stimulation evokes vasodilation in submucosal arterioles by neuronal and nonneuronal mechanisms. Am. J. Physiol. 264, G202–G212 (1993).

  107. 107.

    & Long vasodilator reflexes projecting through the myenteric plexus in guinea-pig ileum. J. Physiol. 553, 911–924 (2003).

  108. 108.

    Vagal sensory receptors and their reflex effects. Physiol. Rev. 53, 159–227 (1973).

  109. 109.

    A method of locating the receptors of visceral afferent fibres. J. Physiol. 124, 166–172 (1954).

  110. 110.

    Impulses in vagal afferent fibres from stretch receptors in the stomach and their role in the peripheral mechanism of hunger. Nature 172, 1194–1195 (1953).

  111. 111.

    et al. Expression of 5-HT3 receptors in the rat gastrointestinal tract. Gastroenterology 123, 217–226 (2002).

  112. 112.

    & Sensitivity to 5-hydroxytryptamine in different afferent subpopulations within mesenteric nerves supplying the rat jejunum. J. Physiol. 509, 717–727 (1998).

  113. 113.

    & Further studies on the blockade of 5-HT depolarizations of rabbit vagal afferent and sympathetic ganglion cells by MDL 72222 and other antagonists. Neuropharmacology 26, 39–48 (1987).

  114. 114.

    & Pharmacological characterization of 5-hydroxytryptamine-induced depolarization of the rat isolated vagus nerve. Br. J. Pharmacol. 90, 229–238 (1987).

  115. 115.

    , , & Intestinal serotonin acts as a paracrine substance to mediate vagal signal transmission evoked by luminal factors in the rat. J. Physiol. 530, 431–442 (2001).

  116. 116.

    et al. Expression of 5-HT3 receptors by extrinsic duodenal afferents contribute to intestinal inhibition of gastric emptying. Am. J. Physiol. Gastrointest. Liver Physiol. 284, G367–G372 (2003).

  117. 117.

    , , & Serotonin released from intestinal enterochromaffin cells mediates luminal non-cholecystokinin-stimulated pancreatic secretion in rats. Gastroenterology 118, 1197–1207 (2000).

  118. 118.

    & Intestinal nutrients elicit satiation through concomitant activation of CCK1 and 5-HT3 receptors. Physiol. Behav. 92, 434–442 (2007).

  119. 119.

    , , & Influence of the 5-HT3 receptor antagonist ondansetron on gastric sensorimotor function and nutrient tolerance in healthy volunteers. Neurogastroenterol. Motil. 23, 444–449, e175 (2011).

  120. 120.

    & Plasticity in the mesenteric afferent response to cisplatin following vagotomy in the rat. J. Auton. Nerv. Syst. 76, 93–98 (1999).

  121. 121.

    Serotonergic mediation of vomiting. J. Pediatr. Gastroenterol. Nutr. 21 (Suppl. 1), S22–S28 (1995).

  122. 122.

    & Mechanism of the anti-emetic activity of 5-HT3 receptor antagonists. Oncology 49, 263–268 (1992).

  123. 123.

    & Serotonin and cholecystokinin activate different populations of rat mesenteric vagal afferents. Neurosci. Lett. 255, 63–66 (1998).

  124. 124.

    , , , & The 5-HT3 receptor antagonist alosetron inhibits the colorectal distention induced depressor response and spinal c-fos expression in the anaesthetised rat. Gut 46, 474–480 (2000).

  125. 125.

    et al. Excitation of rat colonic afferent fibres by 5-HT3 receptors. J. Physiol. 544, 861–869 (2002).

  126. 126.

    , , , & Increased responsiveness of rat colonic splanchnic afferents to 5-HT after inflammation and recovery. J. Physiol. 579, 203–213 (2007).

  127. 127.

    et al. Experimental colitis alters expression of 5-HT receptors and transient receptor potential vanilloid 1 leading to visceral hypersensitivity in mice. Lab. Invest. 92, 769–782 (2012).

  128. 128.

    , , , & Neuronal serotonin regulates growth of the intestinal mucosa in mice. Gastroenterology 143, 408–417.e2 (2012).

  129. 129.

    , & Serotonin and the 5-HT2B receptor in the development of enteric neurons. J. Neurosci. 20, 294–305 (2000).

  130. 130.

    et al. Exogenous serotonin regulates proliferation of interstitial cells of Cajal in mouse jejunum through 5-HT2B receptors. Gastroenterology 133, 897–906 (2007).

  131. 131.

    et al. Tissue-specific mathematical models of slow wave entrainment in wild-type and 5-HT2B knockout mice with altered interstitial cells of Cajal networks. Biophys. J. 98, 1772–1781 (2010).

  132. 132.

    & Serotonin and neuroprotection in functional bowel disorders. Neurogastroenterol. Motil. 19 (Suppl. 2), 19–24 (2007).

  133. 133.

    , , , & 5-HT4 receptor-mediated neuroprotection and neurogenesis in the enteric nervous system of adult mice. J. Neurosci. 29, 9683–9699 (2009).

  134. 134.

    et al. In vitro enhanced differentiation of neural networks in ES gut-like organ from mouse ES cells by a 5-HT4-receptor activation. Biochem. Biophys. Res. Commun. 406, 529–533 (2011).

  135. 135.

    et al. A new possibility for repairing the anal dysfunction by promoting regeneration of the reflex pathways in the enteric nervous system. Am. J. Physiol. Gastrointest. Liver Physiol. 294, G1084–G1093 (2008).

  136. 136.

    et al. A 5-HT4 receptor activation-induced neural plasticity enhances in vivo reconstructs of enteric nerve circuit insult. Neurogastroenterol. Motil. 22, 806–813, e226 (2010).

  137. 137.

    et al. Enhancement of intestinal inflammation in mice lacking interleukin 10 by deletion of the serotonin reuptake transporter. Neurogastroenterol. Motil. 22, 826–834, e229 (2010).

  138. 138.

    et al. Role of serotonin in intestinal inflammation: knockout of serotonin reuptake transporter exacerbates 2, 4, 6-trinitrobenzene sulfonic acid colitis in mice. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G685–G695 (2009).

  139. 139.

    et al. Serotonin has a key role in pathogenesis of experimental colitis. Gastroenterology 137, 1649–1660 (2009).

  140. 140.

    et al. Serotonin activates dendritic cell function in the context of gut inflammation. Am. J. Pathol. 178, 662–671 (2011).

  141. 141.

    Tissue 5-hydroxytryptamine and urinary 5-hydroxyindoleacetic acid after partial or total removal of the gastro-intestinal tract in the rat. J. Physiol. 153, 239–249 (1960).

  142. 142.

    & Observations on the release and turnover rate of 5-hydroxytryptamine in the gastrointestinal tract. J. Pharm. Pharmacol. 11, 618–623 (1959).

  143. 143.

    , & The expanded biology of serotonin. Annu. Rev. Med. 60, 355–366 (2009).

  144. 144.

    et al. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell 135, 825–837 (2008).

  145. 145.

    et al. Pharmacological inhibition of gut-derived serotonin synthesis is a potential bone anabolic treatment for osteoporosis. Nat. Med. 16, 308–312 (2010).

  146. 146.

    et al. Production of serotonin by tryptophan hydroxylase 1 and release via platelets contribute to allergic airway inflammation. Am. J. Respir. Crit. Care Med. 187, 476–485 (2013).

  147. 147.

    , & Life without peripheral serotonin: insights from tryptophan hydroxylase 1 knockout mice reveal the existence of paracrine/autocrine serotonergic networks. ACS Chem. Neurosci. 4, 64–71 (2013).

  148. 148.

    et al. Decreased osteoclastogenesis in serotonin-deficient mice. Proc. Natl Acad. Sci. USA 109, 2567–2572 (2012).

  149. 149.

    et al. Serotonin regulates mammary gland development via an autocrine-paracrine loop. Dev. Cell 6, 193–203 (2004).

  150. 150.

    et al. A transient placental source of serotonin for the fetal forebrain. Nature 472, 347–350 (2011).

  151. 151.

    , & Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol. Biochem. Behav. 71, 533–554 (2002).

  152. 152.

    , , & The terminals of myenteric intrinsic primary afferent neurons of the guinea-pig ileum are excited by 5-hydroxytryptamine acting at 5-hydroxytryptamine-3 receptors. Neuroscience 101, 459–469 (2000).

  153. 153.

    , , & 5-Hydroxytryptamine M-receptor antagonism to prevent cisplatin-induced emesis. Neuropharmacology 25, 959–961 (1986).

  154. 154.

    & Inhibition of cisplatin-induced vomiting by selective 5-hydroxytryptamine M-receptor antagonism. Br. J. Pharmacol. 88, 497–499 (1986).

  155. 155.

    Review article: 5-hydroxytryptamine agonists and antagonists in the modulation of gastrointestinal motility and sensation: clinical implications. Aliment. Pharmacol. Ther. 6, 273–289 (1992).

  156. 156.

    et al. Effects of 5-hydroxytryptamine (serotonin) type 3 antagonists on symptom relief and constipation in nonconstipated irritable bowel syndrome: a systematic review and meta-analysis of randomized controlled trials. Clin. Gastroenterol. Hepatol. 6, 545–555 (2008).

  157. 157.

    , & Efficacy and tolerability of alosetron for the treatment of irritable bowel syndrome in women and men: a meta-analysis of eight randomized, placebo-controlled, 12-week trials. Clin. Ther. 30, 884–901 (2008).

  158. 158.

    & Alosetron and irritable bowel syndrome. Expert Opin. Pharmacother. 4, 2089–2098 (2003).

  159. 159.

    et al. A novel partial 5HT3 agonist DDP733 after a standard refluxogenic meal reduces reflux events: a randomized, double-blind, placebo-controlled pharmacodynamic study. Aliment. Pharmacol. Ther. 27, 404–11 (2008).

  160. 160.

    Drug evaluation: Pumosetrag for the treatment of irritable bowel syndrome and gastroesophageal reflux disease. Curr. Opin. Investig. Drugs 8, 416–422 (2007).

  161. 161.

    , , & Tegaserod for the treatment of irritable bowel syndrome and chronic constipation. Cochrane Database of Systematic Reviews, Issue 1. Art. No.: CD003960 (2008).

  162. 162.

    , , & Cisapride. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use as a prokinetic agent in gastrointestinal motility disorders. Drugs 36, 652–681 (1988).

  163. 163.

    , , , & Effect of tegaserod on gut transit in male and female subjects. Neurogastroenterol. Motil. 17, 821–826 (2005).

  164. 164.

    , & Cisapride accelerates gastric emptying and mouth-to-caecum transit of a barium meal. Eur. J. Clin. Pharmacol. 27, 315–318 (1984).

  165. 165.

    & Peripheral receptor populations involved in the regulation of gastrointestinal motility and the pharmacological actions of metoclopramide-like drugs. Life Sci. 36, 1–14 (1985).

  166. 166.

    & in Proceedings of the Ninth International Symposium of GI Motility (ed. Roman, C.) 527–534 (MTP Press, 1984).

  167. 167.

    & Pharmacological characterization of a neuronal receptor for 5-hydroxytryptamine in guinea pig ileum with properties similar to the 5-hydroxytryptamine receptor. J. Pharmacol. Exp. Ther. 252, 1378–1386 (1990).

  168. 168.

    , & 5-Hydroxytryptamine4 receptor agonists initiate the peristaltic reflex in human, rat, and guinea pig intestine. Gastroenterology 115, 370–380 (1998).

  169. 169.

    , & Effects of cisapride on cholinergic neurotransmission and propulsive motility in the guinea pig ileum. Gastroenterology 96, 1257–1264 (1989).

  170. 170.

    , & Signalling mechanism coupled to 5-hydroxytryptamine4 receptor-mediated facilitation of fast synaptic transmission in the guinea-pig ileum myenteric plexus. Neurogastroenterol. Motil. 15, 523–529 (2003).

  171. 171.

    & 5-HT1A and 5-HT4 receptors mediate inhibition and facilitation of fast synaptic transmission in enteric neurons. Am. J. Physiol. 266, G230–8 (1994).

  172. 172.

    et al. Neurogastroenterology of tegaserod (HTF 919) in the submucosal division of the guinea-pig and human enteric nervous system. Neurogastroenterol. Motil. 20, 80–93 (2008).

  173. 173.

    , , , & Expression and function of 5-HT4 receptors in the mouse enteric nervous system. Am. J. Physiol. Gastrointest. Liver Physiol. 289, G1148–G1163 (2005).

  174. 174.

    , , & The relationship between inflammation-induced neuronal excitability and disrupted motor activity in the guinea pig distal colon. Neurogastroenterol. Motil. 23, 673-e279 (2011).

  175. 175.

    , & 5-HT4 receptor agonists: similar but not the same. Neurogastroenterol. Motil. 20, 99–112 (2008).

  176. 176.

    et al. Systematic review: cardiovascular safety profile of 5-HT4 agonists developed for gastrointestinal disorders. Aliment. Pharmacol. Ther. 35, 745–767 (2012).

  177. 177.

    , & 5-HT4 receptor agonists and δ-opioid receptor antagonists act synergistically to stimulate colonic propulsion. Am. J. Physiol. 275, G979–G983 (1998).

  178. 178.

    et al. Sensory signalling effects of tegaserod in patients with irritable bowel syndrome with constipation. Neurogastroenterol. Motil. 20, 134–141 (2008).

  179. 179.

    , , , & Activation of peripheral 5-HT receptors attenuates colonic sensitivity to intraluminal distension. Neurogastroenterol. Motil. 18, 76–86 (2006).

  180. 180.

    , , & 5-HT2B receptors do not modulate sensitivity to colonic distension in rats with acute colorectal hypersensitivity. Neurogastroenterol. Motil. 18, 343–5 (2006).

  181. 181.

    , , , & Serotonin type-4 receptors modulate the sensitivity of intramural mechanoreceptive afferents of the cat rectum. Neurogastroenterol. Motil. 14, 221–227 (2002).

  182. 182.

    LX-1031, a tryptophan 5-hydroxylase inhibitor, and its potential in chronic diarrhea associated with increased serotonin. Neurogastroenterol. Motil. 23, 193–200 (2011).

  183. 183.

    et al. The tryptophan hydroxylase inhibitor LX1031 shows clinical benefit in patients with nonconstipating irritable bowel syndrome. Gastroenterology 141, 507–516 (2011).

  184. 184.

    et al. Discovery and characterization of novel tryptophan hydroxylase inhibitors that selectively inhibit serotonin synthesis in the gastrointestinal tract. J. Pharmacol. Exp. Ther. 325, 47–55 (2008).

  185. 185.

    , , & Sensory transmission in the gastrointestinal tract. Neurogastroenterol. Motil. 19, 1–19 (2007).

  186. 186.

    Electrophysiological studies of 5-hydroxytryptamine receptors on enteric neurons. Behav. Brain Res. 73, 199–201 (1996).

  187. 187.

    & Opioid, 5-HT1A and α 2 receptors localized to subsets of guinea-pig myenteric neurons. J. Auton. Nerv. Syst. 32, 1–11 (1991).

  188. 188.

    , , & Identification of cells that express 5-hydroxytryptamine1A receptors in the nervous systems of the bowel and pancreas. J. Comp. Neurol. 364, 439–455 (1996).

  189. 189.

    , & Identification and stimulation by serotonin of intrinsic sensory neurons of the submucosal plexus of the guinea pig gut: activity-induced expression of Fos immunoreactivity. J. Neurosci. 12, 235–248 (1992).

  190. 190.

    , , & Actions of 5-hydroxytryptamine on myenteric neurons in guinea pig gastric antrum. Am. J. Physiol. 263, G838–G846 (1992).

  191. 191.

    The physiology and the pathophysiology of the gastric accommodation reflex in man. Verh. K. Acad. Geneeskd. Belg. 62, 183–207 (2000).

  192. 192.

    et al. 5-HT2B receptors play a key role in mediating the excitatory effects of 5-HT in human colon in vitro. Br. J. Pharmacol. 135, 1144–51 (2002).

  193. 193.

    , , , & 5-HT2A receptors: location and functional analysis in intestines of wild-type and 5-HT2A knockout mice. Am. J. Physiol. Gastrointest. Liver Physiol. 282, G877–G893 (2002).

  194. 194.

    et al. Lack of serotonin 5-HT2B receptor alters proliferation and network volume of interstitial cells of Cajal in vivo. Neurogastroenterol. Motil. 22, 462–469 (2010).

  195. 195.

    & Activation of intrinsic afferent pathways in submucosal ganglia of the guinea pig small intestine. J. Neurosci. 20, 3295–3309 (2000).

  196. 196.

    et al. 5-HT7 receptors modulate peristalsis and accommodation in the guinea pig ileum. Gastroenterology 129, 1557–1566 (2005).

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Acknowledgements

This work of the authors is supported by NIH grant DK62267 (to G. M. Mawe). The authors thank Dr B. Lavoie for editorial assistance.

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  1. Department of Neurological Sciences, D403A Given Building, 89 Beaumont Avenue, University of Vermont, Burlington, VT 05405, USA

    • Gary M. Mawe
  2. Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA

    • Jill M. Hoffman

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Both authors contributed equally to all aspects of this manuscript.

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The authors declare no competing financial interests.

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Correspondence to Gary M. Mawe.

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https://doi.org/10.1038/nrgastro.2013.105